The unique observation was made that isotopic fractionation of oxygen occurs during respiration in human subjects. The pattern appears to be affected by anemia, history of smoking, and exercise. Three mechanisms have been postulated to account for the fractionation may be occuring during cellular metabolism such that venous blood returning to the lung is enriched with 180; second, that fractionation occurs in the transfer of oxygen across the alveolar-capillary membrane, and third, that fractionation occurs in the process of oxygen crossing the red cell membrane and being bound to hemoglobin. The aims of this project are as follows: 1. To examine isotopic fractionation of oxygen in vivo in normal human subjects, in individuals with a history of smoking, and in patients with anemia, chronic obstructive lung disease and restrictive lung disease at rest and under different conditions of metabolic rate imposed by exercise. Gas exchange will be measured breath-by-breath. Isotopic fractionation will be measured by mass spectrometry. 2. To measure the kinetics of oxygen isotopic fractionation in vitro accompanying the process of absorption and release of 02 from red blood cells. 3. To measure the isotopic fractionation that occurs across metabolizing tissues by using electrically-stimulated limb exercise in instrumented rabbits. 4. To measure the isotopic fractionation that occurs across the alveolar-capillary membrane using the isolated rabbit lung preparation. It is speculated that elucidating the mechanism of the naturally occuring isotope fractionation of oxygen in human subjects may result in the development of a new noninvasive probe for studying oxygen transfer from the atmosphere to the tissues.